(T1430-01-01) Preparation of a Modified Release Dosage Form of Diltiazem Hydrochloride Using Cation Exchange Resins

Purpose: It was of interest to evaluate the interaction between diltiazem hydrochloride and cation exchange resins with the desire to prepare a modified release oral dosage form.

Methods: The resins that were utilized are cross-linked polystyrenes with sulfonic acid groups attached to it.  The cross linking agent is divinylbenzene and the percentage of cross-linking is 4% and 8% respectively^1-2.  Two forms of the resin were also employed in this study; hydrogen and sodium forms.  The hydrogen form is commercially available, while the sodium form was prepared by applying the displacement method using 2M NaCl solution.  The uptake studies were conducted using the rotating bottle apparatus and the Langmuir-like model was applied to the experimental data.  The drug loading and chemical stability were determined using a validated HPLC method.  The particle size distribution, morphology and the X-ray powder diffraction patterns were all characterized using the appropriate analytical methods (SEM, XRPD and particle size analyzer).  The dissolution studies were performed using USP dissolution apparatus 2 under sink conditions³.

Results: The complexes prepared from the hydrogen form had the highest drug loading.  However, these forms were chemically unstable and decomposed very rapidly due to acid catalysis.  The complexes prepared from the sodium form were highly stable physically and chemically despite showing a significantly lower uptake capacity.  The prepared complexes exhibited the characteristics of amorphous systems and appeared to be spherical with a nonporous surface.  The release profiles revealed initial burst effect followed by a continuous and slow release over 24 hour period.  Excellent correlation was obtained between the initial release rate and drug loading.  The burst effect also decreased with the increase in resin’s particle size and degree of cross-linking.  Excellent results were obtained using the sodium form of the resin with 8% cross-linking and 100-200 mesh.  The release of the drug-resin complex was compared with the USP monograph for extended release capsules and statistical analysis showed that the release correlates very well with the USP monograph.

Conclusion: A modified release dosage form of diltiazem hydrochloride was prepared successfully using drug-resin complex alone.

References: 1. Junyaprsert V B, Manwiwattanakul G. Release profile comparison and stability of diltiazem-resin micorcapsules in sustained release suspensions. Int. J. Pharm., 2008, 352, 81-91.
2. Guo X, Chang R, Hussein M A. Ion-exchange resins as drug delivery carriers. J. Phar. Sci., 2009, 98 (11), 3886-3902.
3. Allaboun Hussein, Alkhamis Khouloud A., Al-Nimry Suhair S. Preparation of sustained release formulation of verapamil hydrochloride using ion exchange resins. AAPS PharmSciTech, 24 (114).

Acknowledgements:

Funding: The authors thank the Deanship of Scientific Research at Jordan University of Science and Technology for their financial support [Grant number 580/2022]
Acknowledgements: The authors thank Ms. Esra'a Zainalabdeen for her valuable comments and efforts.


The uptake isotherm of diltiazem HCl by Dowex 50WX8 Na form, 100-200 mesh at 22oC


Effect of diltiazem HCl uptake on the Initial release rate


Percent cumulative release of diltiazem HCl from Dowex 50WX8, Na form 100-200 mesh in phosphate buffer pH 7.5 at 37 C and 75 rpm.